Straight to the Point—The Novel Strategies to Cure Pediatric AML
Abstract
:1. Introduction
2. Genetic Subtypes and Characterization
3. Genetics Influence the Success of Treatment
3.1. Low-Risk Genetics
3.1.1. RUNX1-RUNX1T1
3.1.2. CBFβ::MYH11
3.1.3. Mutated NPM1 without FLT3/ITD
3.1.4. CEBPA
3.1.5. PML::RARA
3.2. High Risk Genetic
3.2.1. FLT3/ITD Mutation
3.2.2. 11q23/KMT2A Rearrangements
3.2.3. 11p15/NUP98::NSD1 Rearrangements
3.2.4. MNX::ETV6
3.2.5. Aberrations Involving GATA2 and MECOM (EVI1)
3.3. Intermediate Risk
3.3.1. MYST3::CREBBP
3.3.2. Trisomy 21
3.3.3. KIT Mutations
3.3.4. FLT3/TKD
3.3.5. BCR::ABL1
3.3.6. NPM1::MLF1
3.3.7. t(16;21)
3.3.8. RBM15::MKL1
3.3.9. Trisomy 8
3.3.10. Monosomy 7/5 or Del(5q)
3.3.11. Hyperdiploid and Complex Karyotypes
3.4. Mutations That May Significantly Affect Prognosis
Molecular Alteration | Most Common Secondary Cytogenetic Factors | Influence on Prognosis | References |
---|---|---|---|
NPM1 gene mutations | FLT3/ITD Normal karyotype | Improve the prognosis | [12,16,123] |
CEBPA gene mutations | FLT3/ITD GATA2 mutations CBFB::MYH11 Normal karyotype | Improve the prognosis | [12,16,110,123] |
FLT3/ITD | Normal karyotype PML::RARA RUNX1::RUNX1T1 CBFB::MYH11 NUP98::NSD1 DEK::NUP214 trisomy 8 CEBPAdm mutated WT1 | Generally, worsens the prognosis with a few exceptions (e.g., NPM1) | [13,14,54,123] |
Mutated WT1 | NUP98::NSD1 FLT3/ITD CEBPA NPM1 N-RAS K-RAS | Worsens the prognosis | [12,110,123] |
4. New Therapeutic Achievements
4.1. Immunotherapy
4.2. CART-T
4.3. Other Therapeutical Achievements
4.3.1. CPX-351 (Vyxeos®)
4.3.2. HDAC Inhibitors
5. NGS—Predisposition in Pediatric AML
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Molecular Alteration | Frequency in Pediatric AML | Prognosis | References |
---|---|---|---|
t(8;21)(q22;q22) RUNX1::RUNX1T1 | 10–12% | Very good 5-year OS 80–90% | [13,14] |
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB::MYH11 | 10% | Very good 5-year OS 80–90% | [13,14] |
t(15;17)(q24.1;q21.2) PML::RARA | 5–10% 2% in infants | Very good due to advanced therapy 5-year OS 95% 5-year EFS 90% | [15] |
NPM1 gene mutations | 10% (50–60% in adult AML) | Very good 5-year OS 85% Better prognosis without FLT3/ITD | [16,17] |
CEBPA gene double mutations | 5.6% Approximately 70% of CEBPAmt cases | Very good 5-year OS 80% | [18,19] |
CEBPA gene single mutations | 2.4% | Poor 5-year OS 25% | [18,19] |
t(16;21)(q24;q22) RUNX1::CBFA2T3 | 0.2% | Good/intermediate 4-year EFS 77% | [20,21] |
Trisomy 21 | 15% | Good Higher sensitivity to chemotherapeutic agents | [22,23] |
FLT3/ITD mutation | Frequency increases with age 1.5% in infants 7% in children aged 1–5 17% in adolescents and young adults | Poor 5-year OS 30–40% for patients with high allelic ratios | [24,25] |
11q23 (KMT2A) rearrangements | 20% Most frequently in infants | Varies depending on KMT2A fusion partner | [12,26,27,28,29,30] |
t(9;11)(p22;q23) KMT2A::AF9(MLLT3) | 6–9% | Intermediate | A/M |
t(11;19)(q23;p13.1) KMT2A::ELL | 1–2% | Intermediate | A/M |
t(11;19)(q23;p13.3) KMT2A::ENL(MLLT1) | 1–2% | Intermediate | A/M |
t(10;11)(p12;q23) or ins(10;11)(p12;q23q13) KMT2A::AF10(MLLT10) | 2–3% | Poor | A/M |
t(6;11)(q27;q23) KMT2A::AF6(MLLT4) | 1–2% | Poor | A/M |
t(5;11)(q35;p15) NUP98::NSD1 | 3–4% Strong association with FLT3-ITD | Poor 4-year EFS below 10% | [31,32,33] |
t(11;12)(p15;p13) NUP98::KMD5A | 1–2% | Poor 5-year OS 33% | [34,35,36] |
t(7;12)(q36;p13) MNX1::ETV6 | Below 30% Only in infants (<2 y.) | Poor 3-year EFS below 24% | [24,37] |
Monosomy 7 | 4% | Poor 10-year OS 32% 10-year EFS 29% | [13] |
Monosomy 5/del(5q) | 1.2% | Poor 5-yer OS 27% 5-year EFS 23% | [38] |
t(6;9)(p22;q34) DEK::NUP214 | 1.2–4% | Poor 5–10 year OS 30–40% 10-year EFS 30% | [13,38] |
inv(16)(p13.3;q24.3) CBFA2T3::GLIS2 | 2% | Poor 5-year EFS 25–30% | [39] |
inv(3)(q21q26.2) or t(3;3)(q21;q26.2) EVI1 (former MECOM) | 1–2% | Poor Long-term OS < 10% | [11,40,41] |
t(16;21)(p11;q22) FUS::ERG | 0.4% | Poor 4-year EFS 7% | [20,21] |
t(9;22)(q34;q11) BCR::ABL1 | 1% in adults | Uncertain significance Mainly depends on coexisting aberrations | [42,43] |
t(10;11)(p12;q14) PICALM::MLLT10 | <1% | Uncertain significance | [21,44] |
t(8;16)(p11;p13) MYST3::CREBBP | 10% | Spontaneous remission has been observed | [24,45,46] |
KIT gene mutations | 5% overall 25% in CBF-AML population | Uncertain significance May negatively impact response to therapy | [47,48] |
FLT3/TKD mutations | 7% inv(16) AML | Uncertain significance | [49] |
t(1;22)(p13;q13) RBM15::MKL1 | 0.3% | Uncertain significance 5-year EFS 54.5%, 5-year OS 58.2% | [35,50,51] |
t(3;5)(q25;q35 NPM1::MLF1 | <0.5% | Uncertain significance | [42,52,53] |
Trisomy 8 | 3% | Uncertain/discussed significance 5-year EFS 25% | [13,54,55] |
Hyperdiploid karyotype | 11% | Uncertain significance | [56,57] |
Complex karyotype | 8–15% | Uncertain/discussed significance | [13,14] |
Molecular Alteration | Pediatric AML | Adult AML | ||||
---|---|---|---|---|---|---|
Frequency | Prognosis | References | Frequency | Prognosis | References | |
t(8;21)(q22;q22) RUNX1::RUNX1T1 | 10–12% | Very good | [13,14] | 3.5% | Good | [11] |
inv(16)(p13.1q22) or t(16;16)(p13.1;q22) CBFB::MYH11 | 10% | Very good | [13,14] | 3% | Good | [11] |
t(15;17)(q24.1;q21.2) PML::RARA | 5–10% 2% in infants | Very good due to advanced therapy | [15] | 6% | Good | [11] |
NPM1 gene mutations | 10% | Very good Better prognosis without FLT3/ITD | [16,17] | 50–60% | Very good | [58] |
CEBPA gene double mutations | 5.6% | Very good | [18,19] | 5% | Very good | [59,60] |
CEBPA gene single mutations | 2.4% | Poor | [18,19] | 2.3% | Poor | [59,60] |
FLT3/ITD mutation | Frequency increases with age 1.5–17% | Poor | [24,25] | 20–35% | Good/intermediate | [25,61] |
11q23 (KMT2A) rearrangements | 20% | Mostly intermediate and poor | [12,26,27,28,29,30] | 15–20% | Mostly intermediate and poor | [62] |
t(6;9)(p22;q34) DEK::NUP214 | 1.2–4% | Poor | [13,38] | 0.5% | Poor | [11] |
t(9;22)(q34;q11) BCR::ABL1 | The vast majority of adult cases | Uncertain | [42,43] | 1% | Uncertain | [42,43] |
t(8;16)(p11;p13) MYST3::CREBBP | 10% | Uncertain | [24,45,46] | 0.2–0.4% | Uncertain | [63] |
KIT gene mutations | 5% | Uncertain | [47,48] | 12.8–46.1% in CBF leukemia | Uncertain | [64] |
FLT3/TKD mutations | 7% in inv(16) AML | Uncertain | [49] | 28% in inv(16) AML | Uncertain | [49] |
Trisomy 8 | 11% | Uncertain | [13,54,55] | 5% | Uncertain | [11] |
Complex karyotype | 8–15% | Uncertain | [13,14] | 14% | Uncertain | [11] |
t(11;12)(p15;p13) NUP98::KMD5A | 1–2% | Poor | [34,35,36] | Lesions typical of pediatric AML | ||
inv(16)(p13.3;q24.3) CBFA2T3::GLIS2 | 2% | Poor | [39] | |||
t(7;12)(q36;p13) MNX1::ETV6 | Below 30% | Poor | [24,37] | |||
inv(3)(q21q26.2) or t(3;3)(q21;q26.2) EVI1 (former MECOM) | 1–2% | Poor | [11,40,41] | |||
t(1;22)(p13;q13) RBM15::MKL1 | 0.3% | Uncertain | [35,50,51] | |||
t(3;5)(q25;q35 NPM1::MLF1 | <0.5% | Uncertain | [42,52,53] |
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Lejman, M.; Dziatkiewicz, I.; Jurek, M. Straight to the Point—The Novel Strategies to Cure Pediatric AML. Int. J. Mol. Sci. 2022, 23, 1968. https://doi.org/10.3390/ijms23041968
Lejman M, Dziatkiewicz I, Jurek M. Straight to the Point—The Novel Strategies to Cure Pediatric AML. International Journal of Molecular Sciences. 2022; 23(4):1968. https://doi.org/10.3390/ijms23041968
Chicago/Turabian StyleLejman, Monika, Izabela Dziatkiewicz, and Mateusz Jurek. 2022. "Straight to the Point—The Novel Strategies to Cure Pediatric AML" International Journal of Molecular Sciences 23, no. 4: 1968. https://doi.org/10.3390/ijms23041968
APA StyleLejman, M., Dziatkiewicz, I., & Jurek, M. (2022). Straight to the Point—The Novel Strategies to Cure Pediatric AML. International Journal of Molecular Sciences, 23(4), 1968. https://doi.org/10.3390/ijms23041968